2-mercapto-4-substituted thiazoles



United States Patent 2-MERCAPTO-4-SUBSTITUTED THIAZOLES John J. DAmico, Charleston, W. Va., assignor to Monsanto Chemical Company, St. Louis, Mo., a corporation of Delaware N0 Drawing. Application October 5, 1953, Serial No. 384,328

4 Claims. (Cl. 260-302) This invention relates to new and useful Z-mercapto- 4-substituted thiazoles and to methods of making same.

The free mercaptans of this new class of compounds may be represented by the structural formula where R is hydrogen or a short chain alkyl radical. The mercapto hydrogen is active and a. variety of derivatives exhibiting useful properties are obtained by replacing the hydrogen atom by salt forming groups and organic radicals. Examples of salts are zinc, lead, calcium, magnesium, sodium, potasssium, lithium, cadmium, ammonium salts, the substituted ammonium salts such as the cyclohexylammonium, dibutylammonium, isopropylammonium, dimethylammonium, diethylammonium, diisopropylammonium, dodecylammonium salts and the like. Among the organic radicals which may replace hydrogen in the mercapto group and provide for useful compounds within the scope of this invention are CH2OH, acyl groups such as benzoyl, saturated and unsaturated aliphatic groups, aralkyl groups such as benzyl and phenethyl, aromatic groups such as phenyl, tolyl, the chloro substituted, nitro substitutedand similarly substituted benzenoid hydrocarbon groups,

NCCHaC-OR SCH where n is an integer,

C|lN(a1ky1)2 groups, NHz, methylamino, ethylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, n-amylamino, tert-octylamino, cyclohexylamino, a-methyl cyclchexylamino, tat-ethyl cyclohexylamino, benzylamino, a-phenethylamino, furfurylamino, tetrahydrofurfurylamino, B-phenethylamino, 2-hydroxyethylamino, dimethylamino, diethylamino, diisopropylamino, diallylamino, di-n-butylamino, diamylamino, di-B-phenethylamino, di- Z-thienylamino, N-methyl cyclohexylamino, dicyclohexylamino, di-2-cyanoethylamino, morpholinyl, pyrrolidinyl, piperidyl, a-methyl piperidyl, y-methyl piperidyl, thia'zinyl, CHz-NH-aryl groups,

groups where X is oxygen or sulfur.

As illustrative of the new compounds of this invention and the preparation thereof is the following:

EXAMPLE 1 Ethyl-Z-mercapto-4-thiaz0leacetate To an agitated solution containing 113 grams (1.03

ice

moles) of ammonium dithiocarbamate dissolved in 450 grams of water was added 170 grams (1.03 moles) of ethyl 'y-chloroacetoacetate. The reaction was immediate and exothermic, the temperature of the reaction rising from 20 to 56 C. in a period of about 15 minutes. The reaction mix was stirred for an additional 24 hours, then heated at -100 C. for 2 hours, cooled to about 0 C. and filtered. The filter cake was washed with water until the washings were free of chloride. Upon drying there was obtained 199 grams of a white solid melting at -138 C. After recrystallization from benzene the product was found to melt at 139 140 C. Analysis gave 7.01% nitrogen and 31.70% sulfur as compared to 6.89% nitrogen and 31.54% sulfur calculated for CvHsNOzSz.

The intermediate Nl-lzCSSCHzCOCl-IzCOOCzHs can be isolated if desired. After the 24 hour stirring period the reaction mixture was cooled to 03 C. The solid precipitate was removed by filtering, washed with water until the washings were neutral to litmus, then dried at room temperature. The melting point after recrystallizing from benzene was 74-75 C. Analysis gave 6.32% nitrogen and 29.20% sulfur as compared to 6.33% nitrogen and 28.98% sulfur calculated for Crl-InNOaSz. Heating a water suspension of this intermediate at 90-100 C. as described results in formation of the thiazole.

Employing the procedure of Example I but replacing ethyl 'y-chloroacetoacetate with an equimolecular proportion of isopropyl -y-chloroacetoacetate there is obtained isopropyl Z-rnercapto-4-thiazoleacetate.

EXAMPLE 2 2-mercapt0-4-thiazoleacetic acid An agitated solution containing 50.8 grams (0.25 mole) of ethyl 2-mercapto-4-thiazoleacetate, 80 grams (0.5 mole) of 25% aqueous sodium hydroxide and 200 ml. of water was heated at 7080 C. for 3 hours. The reaction mix was cooled to 5 C. and the solution aciditied with concentrated hydrochloric acid maintaining the temperature at 1520 C. The acidified solution was cooled to 5 C., filtered, and the filter cake washed with water until the washings were neutral to litmus. Upon drying there was obtained 39 grams of a tan colored solid, melting with decomposition at 154-155 C. Analysis gave 8.08% nitrogen and 36.63% sulfur as compared to 7.99% nitrogen and 36.60% sulfur calculated for C5H5NO2S2.

EXAMPLE 3 Zinc salt of ethyl 2-mercapt0-4-thiazoleacetate To an agitated solution containing 49 grams (0.24 mole) of ethyl 2-mercapto-4-thiazoleacetate, 38.4 grams (0.24 mole) of 25% aqueous sodium hydroxide and 800 ml. of water was added a solution containing 16.35 grams (0.12 mole) of zinc chloride in 800 ml. of water. The reaction was stirred for about 2 hours and filtered. The filter cake was washed with water until the washings were neutral to litmus. Upon drying a cream colored solid was obtained in a 90.7% yield. Analysis gave 5.97% nitrogen, 26.96% sulfur and 13.41% zinc as compared to 5.96% nitrogen, 27.29% sulfur and 13.91% zinc calculated for C14H1sN2O4S4Zn.

Employing the procedure of Example 3 but replacing zinc chloride with an equimolecular proportion of cadmium sulfate a white solid was obtained in 95.1% yield which on analysis gave 5.25% nitrogen, 24.45% sulfur and 22.30% cadmium as compared to 5.42% nitrogen, 24.81% sulfur and 21.74% cadmium calculated for C14H16N204S4Cd.

3 EXAMPLE 4 Diethyl 2,2'-dit'h-i0bi's -(4-th-iazoleacetate) To a stirred suspension of 50.8 grams (0.25 mole) of ethyl 2-mercapto-4-thiazoleacetate in 300 ml. of water, a solution containing 63 grams (0.275 mole) of ammonium persulfate in 147 grams of water was added dropwise at 2530 C. over a period .of 30 minutes. The reaction mixture was stirred for an additional two hours and then the upper water layer was decanted. The lower oily layer was dissolved in 400 ml. of ethyl ether, the ether extract washed with 200 m1. of 2% sodium hydroxide solution, then with water until the washings were neutral to litmus, dried over sodium sulfate and the ether removed in vacuo. The resulting solid was air dried .at room temperature. The yield was 33 grams (65.4%), M. P. 32-33 C. Analysis gave 7.03% nitrogen and 31.77% sulfur as compared to 6.93% nitrogen and 31.71% sulfur calculated for C14H16N204S4.

EXAMPLE 5 Ethyl 2-(N,Ndiethyldithiocarbamyl) -4-thiaz0'leacetate To a stirred solution containing 50.8 grams (0.25 mole) of ethyl 2-mercapto-4-thiazoleacetate, grams (0.25 mole) of sodium hydroxide, 500 ml. of acetone and 20 grams of water was .added at 2832 C. 38 grams (0.25 mole) of N,N-diethylthiocarbamyl chloride dissolved in 200 ml. of acetone over a period of ten minutes. The reaction mixture was stirred for 4 hours and sodium chloride removed by filtration. The acetone was removed in vacuo, the residue dissolved in 500 ml. of ether, the ether solution washed with 100 ml. of 2% sodium hydroxide solution, then with water until the washings were neutral to litmus, dried over sodium sulfate, and the ether removed in vacuo. The product, a dark amber oil, was obtained in 84.3% yield. Analysis gave 8.69% nitrogen and 29.84% sulfur as compared to 8.80% nitrogen and 30.20% sulfur calculated for Cr2H1sN202S3.

EXAMPLE 6 2,4,6-1'fris (4-.carb ethoxymethyl-2-thiaz0lylmeraapto)-striazine To a stirred solution containing 50.9 grams (0.25 mole) of ethyl 2-mercapto-4-thiazoleacetate, 14 .grams (0.25 mole) ofpotassium hydroxide and 400 ml. of acetone, was added 15.4 grams (0.0833 mole) of cyanuric chlo ride dissolved in 100 ml. .of acetone. An exothermic reaction set in, causing the temperature to rise from 25 to 42 C, over a period of ten minutes. The reaction mix- .ture was heated at 55-,5.6 C. for 5 hours, cooledto room temperature. and the potassium chloride removed by filtration. Upon removal of the acetone in vacuo, the desired product was obtained as a resinous. solid in a yield of 88%. Analysis gave 12.10% nitrogen as compared to 12.27% nitrogen calculatedfor C24H24N606S6.

EXAMPLE 7 2,2-dithiobis (4-thiazoleacetic acid) To an agitated suspension of 7-9 grams (0.45 mole) of 2-mercapto-4-thiazoleacetic acid in 400 ml. of water was added 'dropwise 239 ml. (0.45 mole) of a 30% aqueous solution of ammonium persulfate over a one and one-half hour period at 25-30" C. After stirring for -2 hours longer, the precipitate was filtered and dried at 50 C. The yield was 75 grams (95.6%), M. P. ISO-151 C. with decomposition. After recrystallization from ethyl alcohol there was no change in melting point. Analysis gave 7.88% nitrogen and 36.53% sulfur as compared to 8.04% nitrogen and 36.81% sulfur calculated for EXAMPLE 8 Ethyl 2 (3-chl0r0-2-butenylmercapto) 4-thiaz0leac etate 71 0 ;a stirred solution containing 69 grams (0.34 :mole) of ethyl ,Z-mercapto-4-thiazoleacetate, 19.1 grams (0.34

mole) of potassium hydroxide, 300 ml. of acetone and 10 grams of water, there was added 42.5 grams (0.34 mole) of 1,3-dichl0ro-2-butene. An exothermic reaction set in causing the temperature to rise from 30 to 51 C. over a period of two minutes. The reaction mixture was heated at 55-56 C. for 6 hours, cooled to room temperature and the potassium chloride removed by filtration. The acetone was removed in vacuo, the two layers were separated, and theorganic layer dried over sodium sulfate. The product, an amber colored oil, was obtained .in 67.5% yield. Analysis gave 21.98% sulfur and 11.83% chlorine as compared to 21.98% sulfur and 12.15% chlorine calculated for C11H14C1NO2S2.

EXAMPLE 9 Ethyl 2- (Z-ohloroallylmercapta) -4-th-iaz0leacetate To a stirred solution containing 50.8 grams (0.25 mole) of ethyl 2-mercapto-4-thiazoleacetate, 40 grams (0.25 mole) of 25% aqueous sodium hydroxide and 300ml. of water was added 27.9 grams (0.25 mole) of 2,3-dichlorol-propene. An exothermic reaction set in, causing the temperature to rise from .25-30 C. over a period of one hour. The reaction mixture was stirred for 5 hours, extracted with 500 ml. of ethyl ether, the ether extract washed with 300 m1. of 2% sodium hydroxide, then with water until the washings were neutral to litmus, dried over sodium sulfate and the ether removed in vacuo. The product, an amber oil, was obtained in 59.1% yield. Analysis gave 5.02% nitrogen, 23.09% sulfur and 12.46% chlorine .as compared to 5.04% nitrogen, 23.08% :sulfur and 12.76% chlorine calculated for -C10H12CINQ2S2.

EXAMPLE 10 p Ethyl ,2-.(3echloroallylmercapto) -4-thiazoleacetate Substituting 27.9 grams (0.25 mole) of 1,3-dichloro propene for the 2,'3-dich1oro-1-propene in Example 9 yielded 45 grams (64.9%.) of an amber oil. Analysis gave 490% nitrogen and 22.84% sulfur as compared to 5.04% nitrogen and 23.08% sulfur calculated for CroHrzClNOzSz.

EXAMPLE 1'1 Ethyl .2- (Z-propyny'lmercapto) -4-thiaz0leacetate A solution of sodium .ethyl2mercapto-4-thiazoleacetate was prepared by mixing 50.8 grams (0.25 mole) of ethyl 2-mercapto-44thiazoleacetate, 25 0 grams of water and 40 grams (0.25 mole) of 25% sodium hydroxide. To the stirred solution, 29.8 grams (0.25 mole) of propargyl bromide was added. An exothermic reaction set in, the temperature rising from 30 to 36 C. over a period of five minutes. The reaction mixture was stirred for 5 hours, extracted with 500 ml. ofethyl ether, the ether solution washed with water until the washings were neutral to litmus, dried over sodium sulfate and the ether removed in vacuo. The product, a dark amber oil, was obtained in 49.8% yield. Analysis gave 5.67% nitrogen and 26.33% sulfur .as compared to 5.80% nitrogen and 26.57% sulfur calculated for CmHuNOzSz.

The newcornpounds comprise biological toxicants and accelerators for the vulcanization of rubber. As illustrative of .the vulcanization accelerating properties of the new, compounds .of this invention, the following sulfurvulcanizab'le rubber stocks were compounded comprising:

The stocks so compounded were cured in the usual manner by heating in a press for various periods of time at 144 C. The physical properties obtained are set forth below:

Modulus of Elasticity in Time of losJin. at Elonga- Tensile Ultimate Stock Cure in tions oi at Break Elonga- Mins in 035.] tion,

in. percent 300% 500% 700% As further illustrative of the utility of the novel compounds of this invention but particularly those wherein the mercapto group of the mercaptothiazoles of this invention are replaced by a di-short chain alkyl dithiocarbamyl radical, rubber stocks were compounded comprising:

Stock D Parts by Parts by weight weight Butyl rubber 100 100 Carbon b1ack 54 54 Zinc oxide 5 Stearic acid 1 1 Sulfur 1. 5 1. 5 Tetramethyl thiuram disulfide 1. 0 1.0 Ethyl 2-(N,N-diethyldithiocarbamyl-4-th1azoleacetate 0. 5 2-1VIerc8ptobenzofhiamle 0. 5

The stocks so compounded were cured in the usual manner by heating in a press for difierent periods of time at 330 F. The physical properties obtained are set forth below:

It is intended to cover all changes and modifications of the examples of the invention herein chosen for purposes of disclosure which do not constitute departure from the spirit and scope of the invention.

What is claimed is:

1. As new compounds 2-mercapto-4-substituted thiazoles of the structural formula 5 LR where R is selected from the group consisting of hydrogen and lower alkyl radicals and where R is selected from the group consisting of hydrogen, metal salt forming groups, ammonium, and cyclohexyl, alkyl and dialkyl ammonium radicals containing less than 13 carbon atoms.

2. As new compounds 2-mercapto-4-substituted thiazoles of the structural formula c in where R is a lower alkyl radical.

3. As a new compound ethyl 2-mercapto-4-thiazoleacetate.

4. As a new compound 2-mercapto-4-thiazoleacetic acid.

References Cited in the file of this patent UNITED STATES PATENTS Buchman Oct. 25, 1938 Mathes Apr. 9, 1940 OTHER REFERENCES Cook et 21.: Chem. Abst., vol. 43, col. 1398 (1949). Swain: Chem. Abst., vol. 44, col. 3976 (1950).

Levi: Chem. Abst., vol. 26, page 1602 (1932). Ubaldini et a1.: Chem. Abst., vol. 38, col. 5827' (1944). 

1. AS NEW COMPOUNDS 2-MERCAPTO-4-SUBSTITUTED THIAZOLES OF THE STRUCTURAL FORMULA 